Gong Yanqing, Agani Faton H
Dept. of Anatomy, School of Medicine, Case Western Reserve Univ., 10900 Euclid Ave., Cleveland, OH 44106, USA.
Am J Physiol Cell Physiol. 2005 May;288(5):C1023-9. doi: 10.1152/ajpcell.00443.2004.
Hypoxia-inducible factor-1 (HIF-1) is a key regulator of cellular responses to reduced oxygen availability. The contribution of mitochondria in regulation of HIF-1alpha in hypoxic cells has received recent attention. We demonstrate that inhibition of electron transport complexes I, III, and IV diminished hypoxic HIF-1alpha accumulation in different tumor cell lines. Hypoxia-induced HIF-1alpha accumulation was not prevented by the antioxidants Trolox and N-acetyl-cysteine. Oligomycin, inhibitor of F(0)F(1)-ATPase, prevented hypoxia-induced HIF-1alpha protein accumulation and had no effect on HIF-1alpha induction by hypoxia-mimicking agents desferrioxamine or dimethyloxalylglycine. The inhibitory effect of mitochondrial respiratory chain inhibitors and oligomycin on hypoxic HIF-1alpha content was pronounced in cells exposed to hypoxia (1.5% O(2)) but decreased markedly when cells were exposed to severe oxygen deprivation (anoxia). Taken together, these results do not support the role for mitochondrial reactive oxygen species in HIF-1alpha regulation, but rather suggest that inhibition of electron transport chain and impaired oxygen consumption affect HIF-1alpha accumulation in hypoxic cells indirectly via effects on prolyl hydroxylase function.
缺氧诱导因子-1（HIF-1）是细胞对氧供应减少反应的关键调节因子。线粒体在缺氧细胞中对HIF-1α的调节作用最近受到了关注。我们证明，抑制电子传递复合物I、III和IV可减少不同肿瘤细胞系中缺氧诱导的HIF-1α积累。抗氧化剂托可索仑（Trolox）和N-乙酰半胱氨酸并不能阻止缺氧诱导的HIF-1α积累。F（0）F（1）-ATP酶抑制剂寡霉素可阻止缺氧诱导的HIF-1α蛋白积累，且对缺氧模拟剂去铁胺或二甲基草酰甘氨酸诱导的HIF-1α没有影响。线粒体呼吸链抑制剂和寡霉素对缺氧HIF-1α含量的抑制作用在暴露于缺氧（1.5% O₂）的细胞中很明显，但当细胞暴露于严重缺氧（无氧）时则明显降低。综上所述，这些结果不支持线粒体活性氧在HIF-1α调节中的作用，而是表明电子传递链的抑制和氧消耗受损通过对脯氨酰羟化酶功能的影响间接影响缺氧细胞中HIF-1α的积累。
